ABSTRACT Age-related cognitive decline and neurodegenerative disorders present a major public health challenge as lifespans are increasing. APOE genotype is an important risk factor for cognitive decline in aging, as APOE4 is associated with cognitive dysfunction compared to APOE3 in older adults. Current research suggests that APOE4 affects synaptic function through pathways that include oxidative stress, lower neurotrophic growth factor production, neuroinflammation and blood-brain barrier disruption. Therefore, identifying treatments that target these pathways may provide an opportunity to reduce APOE4 associated cognitive decline during aging. Further, as aging and APOE4 are major risk factors for Alzheimer's disease (AD), such a treatment may help delay the onset of AD. DHA (docosahexaenoic acid, 22:6, n-3) is an essential fatty acid that is important for learning and memory and acts through similar pathways that are disrupted by APOE4. DHA deficiency is associated with cognitive decline in aging, which may be particularly pronounced with APOE4. Indeed, current research suggests that APOE4 lowers the amount of DHA delivered to cells in the brain. However, observation studies and clinical trials with DHA supplements have produced mixed and largely disappointing results for preventing cognitive decline in aging and AD, including in reports stratified by APOE genotype. An important contributing factor is that the currently available molecular forms of DHA (fish oil, krill oil and the prescription drugs Epanova and Lovaza) may not enrich brain DHA levels sufficiently to improve neuronal function. Indeed, these forms are not converted in high amounts to lysophosphatidylcholine (LPC)-DHA, which is the main form of DHA that crosses the blood-brain barrier into the brain. Thus, optimizing molecular forms of DHA to enrich brain DHA may be particularly beneficial for APOE4 carriers at reducing age-related cognitive decline. We have developed a novel strategy to raise plasma LPC-DHA levels by feeding tailored phospholipids in the form of sn-1 DHA phospholipids (LPC-DHA). Our rationale was that LPC-DHA will escape the hydrolysis by pancreatic enzymes, and be absorbed as phosphatidylcholine DHA, which is converted to LPC-DHA and delivered to the brain efficiently. In support of this approach, we recently demonstrated in wild type mice that 40 mg of LPC-DHA/kg/day delivered for 30 days results in improved memory and a 2-fold increase in brain DHA levels, whereas free DHA did not. Importantly, our preliminary data suggest that LPC-DHA can enrich brain DHA levels in mice that express human APOE4. We propose to advance these data and test the hypothesis that dietary LPC-DHA will enrich brain DHA and reduce age-related cognitive decline in mice that express APOE4. Our experiments will evaluate the ability of LPC-DHA to reduce age-related cognitive decline and improve synaptic function in APOE3 and APOE4-targeted replacement mice (Aim 1). We will explore the possibility that LPC-DHA treatment enriches the DHA content of brain tissue and modulates pathways in the brain that are important for cognitive function (Aim 2).